I am currently an Assistant Professor in the Division of Gastroenterology, Hepatology, and Nutrition at The Children's Hospital of Philadelphia (CHOP), having completed a Gastroenterology fellowship at CHOP in June 2009. In order to obtain training in translational research, I completed a Masters of Translational Research (MTR) at the Institute of Translational and Therapeutic Medicine (ITMAT), at the University of Pennsylvania (UPENN) School of Medicine. I am now applying for a Mentored Patient-Oriented Research Career Development (K23) Award to develop advanced research skills in IBD to become an independent investigator in translational research focusing on very early-onset inflammatory bowel disease (VEO-IBD). This training will afford me the opportunity to gain valuable experience in conducting patient-oriented research linking basic science advances with clinical phenotype to generate an approach in the evaluation and treatment of these children. My short-term goals are to obtain additional training and experience in the design, conduct and analyses of patient-oriented translational research studying our unique VEO-IBD patient population. My long- term goal is to lead prospective translational studies in this cohort, collaborating and integrating genomics, microbiology and immunology to individualize therapy for these patients. Following graduation from fellowship, under the guidance of my mentors, I led a study on the oral microbiome in pediatric CD. This allowed me to develop bench research skills and begin to cultivate skills in study design and data analysis. In concert with this theme, with my mentor Gary Wu, MD I wrote a review on the Gut Microbiota, environment and diseases of modern society, and on IBD and the Microbiome. During this time, I became interested in the very young children with IBD, both by the severe presentation of disease as well as by the lack of consensus of approach in their care. In addition to my goal of studying the microbiome of these children, I became interested in understanding the strong genetic contribution to their disease. My evaluation on their poor response to infliximab therapy begins to address this question and the data has been submitted for publication. My recent pilot project utilizing whole exome sequencing to detect novel and rare causal variants of disease further explores this question and generated the preliminary data for this project. These experiences have helped shaped this proposed K23 and my career goals. I am now in need of further training to achieve these goals as my future research as well as optimal care of this cohort, centers on the integration of genomic, microbiome, immunologic and phenotypic analysis of patients with VEO-IBD. Therefore, I along with my mentors, have designed the mentored scientific and educational program proposed in this K-23, consisting of (1) formal didactic instruction in areas germane to my research interests, such as genomics and immunology (2) mentored research preceptorship with senior faculty in computational genomics, epidemiology and immunology (3) structured collaboration with expert faculty in related fields (4) training in the responsible conduct of research and ethics of genetic research (5) completion of the Research Plan described in this application (6) additional developmental activities at UPENN and CHOP. Under the close mentorship and guidance of senior faculty, I will perform increasingly independent clinical research. In the later years of this K23 Award, I will submit applications for investigator-initiated research, such as R01s. An integral part of my career development will be the mentorship provided by senior clinical investigators. Dr. Marcella Devoto, PhD., is the primary Sponsor of this Research Career Development Award. The proposal is described below. Inflammatory bowel disease occurring in children less than 6 years of age is known as VEO-IBD. Children with VEO-IBD often have more severe symptoms and a greater extent of GI tract involvement than adults. The severity of illness and young age of presentation suggest a more pronounced genetic and dysregulated immune response than in older patients. For example, variants in the IL10R gene have been identified in several patients with severe VEO-IBD, for whom stem cell transplantation, rather than anti-TNF ? therapy, is now indicated. However, the causes of most VEO-IBD cases are unknown. Thus, identification of these and other immunodeficiencies is critically important to the development of clinical algorithms used to treat the VEO-IBD population. The population of VEO-IBD patients seen at CHOP presents an opportunity to address substantive questions regarding the clinical course of VEO-IBD and to identify subgroups of patients with specific genetic abnormalities. The goal of this proposal is to test the overall hypothesis that VEO-IBD represents a distinct form of IBD with a high risk of severe, aggressive disease and is caused by a distinct set of genetic variants than later-onset IBD. If successful, this proposal will have a major impact on the diagnosis and treatment of children with EO-IBD and may also shed light on the causes of IBD in general. Our specific goals are: 1) To determine whether VEO-IBD is associated with a more severe short term disease course defined as the need for early surgery or refractory growth failure, than later onset pediatric IBD; 2) To define the role of known IBD loci in VEO-IBD and identify new causal mutations; 3) To identify those genetic and phenotypic predictors of early surgery in pediatric IBD. Through melding of new technology, genomics, IBD, epidemiology and immunology, and ultimately the microbiome, the proposed research will be an outstanding platform from which I will be able to build an independent line of research.